{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T13:03:34Z","timestamp":1791378214413,"version":"4.3.2"},"reference-count":40,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T00:00:00Z","timestamp":1605139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004271","name":"Sapienza Universit\u00e0 di Roma","doi-asserted-by":"publisher","award":["AR11916B4BBEA472"],"award-info":[{"award-number":["AR11916B4BBEA472"]}],"id":[{"id":"10.13039\/501100004271","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>The FLICE-inhibitory protein (c-FLIPL) (55 kDa) is expressed in numerous tissues and most abundantly in the kidney, skeletal muscles and heart. The c-FLIPL has a region of homology with caspase-8 at the carboxy-terminal end which allows the molecule to assume a tertiary structure similar to that of caspases-8 and -10. Consequently, c-FLIPL acts as a negative inhibitor of caspase-8, preventing the processing and subsequent release of the pro-apoptotic molecule active form. The c-FLIP plays as an inhibitor of apoptosis induced by a variety of agents, such as tumor necrosis factor (TNF), T cell receptor (TCR), TNF-related apoptosis inducing ligand (TRAIL), Fas and death receptor (DR). Increased expression of c-FLIP has been found in many human malignancies and shown to be involved in resistance to CD95\/Fas and TRAIL receptor-induced apoptosis. We wanted to verify an investigative protocol using FLIP to make a differential diagnosis between skin sulcus with vitality or non-vital skin sulcus in hanged subjects and those undergoing simulated hanging (suspension of the victim after murder). The study group consisted of 21 cases who died from suicidal hanging. The control group consisted of traumatic or natural deaths, while a third group consisted of simulated hanging cases. The reactions to the Anti-FLIP Antibody (Abcam clone-8421) was scored for each section with a semi-quantitative method by means of microscopic observation carried out with confocal microscopy and three-dimensional reconstruction. The results obtained allow us to state that the skin reaction to the FLIP is extremely clear and precise, allowing a diagnosis of unequivocal vitality and a very objective differentiation with the post-mortal skin sulcus.<\/jats:p>","DOI":"10.3390\/diagnostics10110938","type":"journal-article","created":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T10:00:32Z","timestamp":1605175232000},"page":"938","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Hypo-Expression of Flice-Inhibitory Protein and Activation of the Caspase-8 Apoptotic Pathways in the Death-Inducing Signaling Complex Due to Ischemia Induced by the Compression of the Asphyxiogenic Tool on the Skin in Hanging Cases"],"prefix":"10.3390","volume":"10","author":[{"given":"Aniello","family":"Maiese","sequence":"first","affiliation":[{"name":"Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, 56126 Pisa PI, Italy"},{"name":"IRCCS (Istituto di Ricerca e Cura a Carattere Scientifico) Neuromed Mediterranean Neurological Institute, Via Atinense 18, 86077 Pozzilli IS, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"De Matteis","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome RM, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Bolino","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome RM, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Turillazzi","sequence":"additional","affiliation":[{"name":"Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, 56126 Pisa PI, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0358-7965","authenticated-orcid":false,"given":"Paola","family":"Frati","sequence":"additional","affiliation":[{"name":"IRCCS (Istituto di Ricerca e Cura a Carattere Scientifico) Neuromed Mediterranean Neurological Institute, Via Atinense 18, 86077 Pozzilli IS, Italy"},{"name":"Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome RM, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1686-3236","authenticated-orcid":false,"given":"Vittorio","family":"Fineschi","sequence":"additional","affiliation":[{"name":"IRCCS (Istituto di Ricerca e Cura a Carattere Scientifico) Neuromed Mediterranean Neurological Institute, Via Atinense 18, 86077 Pozzilli IS, Italy"},{"name":"Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome RM, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S1535-6108(02)00024-7","article-title":"A matter of life and death","volume":"1","author":"Green","year":"2002","journal-title":"Cancer Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.biocel.2009.11.015","article-title":"Cellular FLICE-inhibitory protein (c-FLIP) signalling: A key regulator of receptor-mediated apoptosis in physiologic context and in cancer","volume":"42","author":"Bagnoli","year":"2010","journal-title":"Int. J. Biochem. Cell. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"8247","DOI":"10.1128\/MCB.21.24.8247-8254.2001","article-title":"FLICE-inhibitory proteins: Regulators of death receptor-mediated apoptosis","volume":"21","author":"Krueger","year":"2001","journal-title":"Mol. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1517\/14728222.7.4.559","article-title":"Cellular FLICE-inhibitory protein: An attractive therapeutic target?","volume":"7","author":"Micheau","year":"2003","journal-title":"Expert Opin. Ther. Targets."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S0014-5793(01)03222-7","article-title":"The short splice form of Casper\/c-FLIP is a major cellular inhibitor of TRAIL-induced apoptosis","volume":"510","author":"Bin","year":"2002","journal-title":"FEBS Lett."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4742","DOI":"10.1128\/MCB.25.11.4742-4751.2005","article-title":"FLIP protects against hypoxia\/reoxygenation-induced endothelial cell apoptosis by inhibiting Bax activation","volume":"25","author":"Wang","year":"2005","journal-title":"Mol. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2665","DOI":"10.1172\/JCI26252","article-title":"Caspases: Pharmacological manipulation of cell death","volume":"115","author":"Lavrik","year":"2005","journal-title":"J. Clin. Invest."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6216","DOI":"10.1038\/onc.2008.299","article-title":"FLIP and the death effector domain family","volume":"27","author":"Yu","year":"2008","journal-title":"Oncogene"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/S0960-9822(00)00512-1","article-title":"The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways","volume":"10","author":"Kataoka","year":"2000","journal-title":"Curr. Biol."},{"key":"ref_10","unstructured":"Safa, A.R. (2003). Roles of c-FLIP in Apoptosis, Necroptosis, and Autophagy. J. Carcinog. Mutagen., 003."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/sj.cdd.4400370","article-title":"Cell death attenuation by \u2018Usurpin\u2019, a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex","volume":"5","author":"Rasper","year":"1998","journal-title":"Cell Death Differ."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S0092-8674(00)80085-9","article-title":"Induction of apoptotic program in cell-free extracts: Requirement for dATP and cytochrome c","volume":"86","author":"Liu","year":"2006","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.cell.2006.01.021","article-title":"The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover","volume":"124","author":"Chang","year":"2006","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1038\/s41418-020-0489-0","article-title":"Dissecting DISC regulation via pharmacological targeting of caspase-8\/c-FLIPL heterodimer","volume":"27","author":"Hillert","year":"2020","journal-title":"Cell Death Differ."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"857","DOI":"10.3389\/fonc.2019.00857","article-title":"Down Regulation of c-FLIPL Enhance PD-1 Blockade Efficacy in B16 Melanoma","volume":"9","author":"Wang","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"20011","DOI":"10.1038\/s41598-019-56682-7","article-title":"Regulation of miRNAs as new tool for cutaneous vitality lesions demonstration in ligature marks in deaths by hanging","volume":"9","author":"Neri","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_17","first-page":"1539","article-title":"Tryptase, CD15 and IL-15 as reliable markers for the determination of soft and hard ligature marks vitality","volume":"25","author":"Turillazzi","year":"2010","journal-title":"Histol. Histopathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6470","DOI":"10.1002\/jcp.26585","article-title":"Down-regulation of intracellular anti-apoptotic proteins, particularly c-FLIP by therapeutic agents; the novel view to overcome resistance to TRAIL","volume":"233","author":"Hassanzadeh","year":"2018","journal-title":"J. Cell Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s00414-007-0208-0","article-title":"Confocal laser scanning microscopy. Using new technology to answer old questions in forensic investigations","volume":"122","author":"Turillazzi","year":"2008","journal-title":"Int. J. Legal Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/S0952-7915(98)80223-9","article-title":"Inhibition of fas death signals by FLIPs","volume":"10","author":"Tschopp","year":"1998","journal-title":"Curr. Opin. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8541","DOI":"10.1128\/MCB.24.19.8541-8555.2004","article-title":"Direct repression of FLIP expression by c-myc is a major determinant of TRAIL sensitivity","volume":"24","author":"Ricci","year":"2004","journal-title":"Mol. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1093\/carcin\/bgq193","article-title":"ATM kinase activity modulates cFLIP protein levels: Potential interplay between DNA damage signalling and TRAIL-induced apoptosis","volume":"31","author":"Stagni","year":"2010","journal-title":"Carcinogenesis"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s10529-006-9213-5","article-title":"Down-regulation of c-FLIP increases reactive oxygen species, induces phosphorylation of serine\/threonine kinase Akt, and impairs motility of cancer cells","volume":"29","author":"Shim","year":"2007","journal-title":"Biotechnol. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7753","DOI":"10.1038\/sj.onc.1208051","article-title":"FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells","volume":"23","author":"Rippo","year":"2004","journal-title":"Oncogene"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/path.835","article-title":"Increased expression of cFLIP(L) in colonic adenocarcinoma","volume":"194","author":"Ryu","year":"2001","journal-title":"J. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3822","DOI":"10.1158\/1078-0432.CCR-11-3277","article-title":"Elevation of c-FLIP in castrate-resistant prostate cancer antagonizes therapeutic response to androgen receptor-targeted therapy","volume":"18","author":"McCourt","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Dettmeyer, R.B. (2018). Forensic Histopathology: Fundamentals and Perspectives, Springer.","DOI":"10.1007\/978-3-319-77997-3"},{"key":"ref_28","first-page":"280","article-title":"Downregulation of c FLIP and upregulation of DR 5 by cantharidin sensitizes TRAIL mediated apoptosis in prostate cancer cells via autophagy flux","volume":"46","author":"Nazim","year":"2020","journal-title":"Int. J. Mol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1126\/scisignal.2003845","article-title":"The FLIP Side of Life","volume":"6","author":"Silke","year":"2013","journal-title":"Sci. Signal."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/1475-2867-12-54","article-title":"Down-regulation of cellular FLICE-inhibitory protein (Long Form) contributes to apoptosis induced by Hsp90 inhibition in human lung cancer cells","volume":"12","author":"Wang","year":"2012","journal-title":"Cancer Cell Int."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1097\/PAF.0000000000000322","article-title":"Diagnosis of Vitality in Skin Wounds in the Ligature Marks Resulting from Suicide Hanging","volume":"38","author":"Gimenez","year":"2017","journal-title":"Am. J. Forensic Med. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1097\/PAF.0b013e3181c17ec2","article-title":"Hemorrhagic lividity of the neck: Controlled induction of postmortem hypostatic hemorrhages","volume":"30","author":"Pollanen","year":"2009","journal-title":"Am. J. Forensic Med. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s00414-011-0622-1","article-title":"Haemorrhages into the back and auxiliary breathing muscles after death by hanging","volume":"125","author":"Schulz","year":"2011","journal-title":"Int. J. Legal Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/0379-0738(91)90146-A","article-title":"A new staining method for constriction marks in skin","volume":"50","author":"Niu","year":"1991","journal-title":"Forensic Sci. Int."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1177\/0025817219861277","article-title":"The forensic approach to plastic bag suffocation: Case reports and review of the literature","volume":"87","author":"Santoro","year":"2019","journal-title":"Med. Leg. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.forsciint.2019.05.055","article-title":"The Troponin-I fast skeletal muscle is reliable marker for the determination of vitality in the suicide hanging","volume":"301","author":"Maiese","year":"2019","journal-title":"Forensic Sci. Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1097\/00000433-199803000-00017","article-title":"Typical homicide ritual of the Italian Mafia (incaprettamento)","volume":"19","author":"Fineschi","year":"2019","journal-title":"Am. J. Forensic Med. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1007\/s00414-018-1780-1","article-title":"Forensic application of epidermal AQP3 expression to determination of wound vitality in human compressed neck skin","volume":"132","author":"Ishida","year":"2018","journal-title":"Int. J. Legal Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1097\/PAF.0000000000000199","article-title":"Evaluation of Vitality in the Experimental Hanging Model of Rats by Using Immunohistochemical IL-1\u03b2 Antibody Staining","volume":"36","author":"Balandiz","year":"2015","journal-title":"Am. J. Forensic Med. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/S0379-0738(03)00210-X","article-title":"Fatal trauma to the neck: Immunohistochemical study of local injuries","volume":"135","author":"Fieguth","year":"2003","journal-title":"Forensic Sci. Int."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/10\/11\/938\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:32:17Z","timestamp":1760178737000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/10\/11\/938"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,12]]},"references-count":40,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["diagnostics10110938"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics10110938","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,12]]}}}